Project Grant R01HL170612

INHALABLE STEM CELL EXOSOME THERAPY FOR CARDIAC INJURY - PROJECT SUMMARY MYOCARDIAL INFARCTION (MI) HAPPENS WHEN THE BLOOD FLOW IN ONE OR MORE CORONARY VESSELS ARE BLOCKED. DUE TO THE LIMITED REGENERATIVE CAPABILITY OF THE HEART, THIS CAN LEAD TO LIFE-THREATENING HEART FAILURE (HF). END- STAGE HF USUALLY REQUIRES HEART TRANSPLANTATION. STEM CELLS HAVE BEEN STUDIED AS PROMISING THERAPEUTICS FOR CARDIAC REPAIR POST-MI IN NUMEROUS PRE-CLINICAL STUDIES AND A VARIETY OF CLINICAL TRIALS. HOWEVER, THE TRANSLATION OF STEM CELL THERAPY FOR HEART DISEASES FROM BENCH TO BEDSIDE IS STILL HAMPERED BY CELL SOURCES, CELL VIABILITY, UNCERTAIN DELIVERY EFFICIENCY AND IMMUNE REJECTION. IT HAS BEEN WELL ESTABLISHED THAT MANY TYPES OF ADULT STEM CELLS EXERT THEIR BENEFICIAL EFFECTS MAINLY THROUGH SECRETION OF PARACRINE FACTORS THAT PROMOTE ENDOGENOUS HEART REPAIR. IN RECENT YEARS, MANY IN THE FIELD INCLUDING OUR GROUP HAVE GRAVITATED TOWARD THE STUDY OF EXTRACELLULAR VESICLES (EVS) RELEASED FROM STEM CELLS, WHICH CONTAIN THE BIOLOGICALLY ACTIVE COMPONENTS AND HAVE COMPARABLE THERAPEUTIC EFFECTS BUT MINIMAL IMMUNOGENICITY, SUGGESTING THE POSSIBILITY OF A PROMISING ALTERNATIVE TO STEM CELL THERAPIES. IN THE PAST 8 YEARS, OUR GROUP HAS BEEN DEVELOPING SECRETOME AND EXOSOMES (EXOS; 30-150 NM EXTRACELLULAR VESICLES)- BASED THERAPIES FOR LUNG AND HEART DISEASES, AND WE HAVE SUCCESSFULLY SHOWN THEIR THERAPEUTIC EFFICACY IN SEVERAL PRE-CLINICAL STUDIES. AMONG THEM, TRANSPLANTATION OF LUNG SPHEROID CELLS (LSCS) HAS BEEN ADVANCED TO A FIRST-IN-MAN CLINICAL TRIAL IN PATIENTS WITH LUNG FIBROTIC DISEASE AND LSC-SECRETOME/EXOSOME HAS RECENTLY BEEN APPROVED FOR ARDS-ASSOCIATED COVID-19. GIVEN THE SAFETY AND GREAT REGENERATIVE POTENTIAL OF LSC PRODUCTS, WE PERFORMED RNA SEQUENCING IN LSC-EXOS AND FOUND VARIOUS THERAPEUTIC MIRNAS ENRICHED IN THEM. THE MOST ABUNDANT OF THEM, MIR-100, WERE SHOWN TO BENEFIT NEOVASCULARIZATION AND HEART FUNCTION IN SEVERAL STUDIES. HOWEVER, MOST EXOSOME THERAPIES FOR MI TREATMENT HAVE THEIR INTRINSIC LIMITATIONS, SUCH AS THE SAFETY AND EFFICIENCY OF DELIVERY ROUTES, DELIBERATELY HINDERED THE CLINICAL FEASIBILITY. MOREOVER, SINCE THE HALF-LIFE OF EXOS IN VIVO IS SHORT, REPEATED DOSING OF EXOSOMES IS REQUIRED FOR LONG-TERM HEART TREATMENT. OUR MAIN GOAL OF CURRENT PROPOSAL IS TO DEVELOP INHALATION DELIVERY, AS A REPEATABLE AND NONINVASIVE ROUTE THAT MAY BOOST THE EFFICACY AND TRANSLATABILITY OF LSC-EXO TREATMENT TO MI. AIM 1. ESTABLISH THE THERAPEUTIC BENEFITS OF REPEATED INHALATION DELIVERY OF LSC-EXO IN A MOUSE MODEL OF MI. AIM 2. EXPLORE AND VALIDATE THE MECHANISM OF ACTION IN LSC-EXO INHALATION TREATMENT. AIM 3. DETERMINE THE SAFETY AND EFFICACY OF LSC-EXO INHALATION TREATMENT IN A CLINICALLY-RELEVANT PORCINE MODEL OF MI. THE DEVELOPMENT OF INHALABLE CELL-FREE THERAPEUTICS HAS THE POTENTIAL TO REVOLUTIONIZE CURRENT REGENERATIVE MEDICINE PRACTICE. THE RESULTS OF THIS PROJECT, IF SUCCESSFUL, ARE EXPECTED TO DRAMATICALLY IMPACT CURRENT TREATMENT OPTIONS FOR MI PATIENTS. THESE STUDIES WILL HELP VALIDATE THE USE OF INHALABLE EXOSOMES AS A NEW THERAPEUTIC MODALITY FOR HEART DISEASE, AND LAY THE GROUND FOR FUTURE IND-ENABLED HUMAN TRIALS.